chr2-130598707-A-AGC

Variant names:

• chr2-130598707-A-AGC
• NM_032545.4:c.181_182insGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032545.4(CFC1):​c.181_182insGC​(p.Val61GlyfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_032545.4 frameshift
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.170
• Publications: 0 publications found

Genes affected

CFC1 (HGNC:18292): (cryptic, EGF-CFC family member 1) This gene encodes a member of the epidermal growth factor (EGF)- Cripto, Frl-1, and Cryptic (CFC) family, which are involved in signalling during embryonic development. Proteins in this family share a variant EGF-like motif, a conserved cysteine-rich domain, and a C-terminal hydrophobic region. The protein encoded by this gene is necessary for patterning the left-right embryonic axis. Mutations in this gene are associated with defects in organ development, including autosomal visceral heterotaxy and congenital heart disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

CFC1 Gene-Disease associations (from GenCC):

• heterotaxy, visceral, 2, autosomal

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ENSG00000296255 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032545.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFC1	NM_032545.4	MANE Select	c.181_182insGC	p.Val61GlyfsTer2	frameshift	Exon 3 of 6	NP_115934.1	P0CG37
	CFC1	NM_001270420.2		c.181_182insGC	p.Val61GlyfsTer2	frameshift	Exon 3 of 5	NP_001257349.1	A0A087WWV2
	CFC1	NM_001270421.2		c.181_182insGC	p.Val61GlyfsTer2	frameshift	Exon 3 of 4	NP_001257350.1	A0A087WX98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFC1	ENST00000259216.6	TSL:1 MANE Select	c.181_182insGC	p.Val61GlyfsTer2	frameshift	Exon 3 of 6	ENSP00000259216.5	P0CG37
	CFC1	ENST00000615342.4	TSL:5	c.181_182insGC	p.Val61GlyfsTer2	frameshift	Exon 3 of 5	ENSP00000480526.1	A0A087WWV2
	CFC1	ENST00000621673.4	TSL:2	c.181_182insGC	p.Val61GlyfsTer2	frameshift	Exon 3 of 4	ENSP00000480843.1	A0A087WX98

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461212 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726948

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60266

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Heterotaxy, visceral, 2, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-131356280;